Delivery of drug amines through an inhalation route

ABSTRACT

The present invention relates to the delivery of drug amines through an inhalation route. Specifically, it relates to aerosols containing drug amines that are used in inhalation therapy. In one aspect of the present invention, a method of delivering an amine drug in an aerosol form is provided. The method comprises: a) heating a coating, which includes an amine drug salt on a substrate contained in a device to a temperature sufficient to volatilize the amine drug from the coating, b) by said heating, forming an amine drug vapor, and c) during said heating, drawing air through said device, condensing said vapor to form aerosol particles containing less than 10% degradation products of the compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional applicationSer. No. 60/380,819 entitled “Delivery of Drug Amines Through anInhalation Route,” filed May 13, 2002, Rabinowitz and Zaffaroni, theentire disclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of drug aminesthrough an inhalation route. Specifically, it relates to aerosolscontaining drug amines that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

[0003] There are a number of compounds containing amines that arecurrently marketed as drugs. In certain circumstances, the presence ofsuch functionality, however, can prevent effective drug delivery. Thisphenomenon could be due to a range of effects, including poor solubilityand instability.

[0004] Inhaled drugs, however, have the potential to enter the systemiccirculation and thereby circumvent a number of the problems associatedwith oral and other drug delivery methods. Moreover, by manipulation ofparticle size and/or density, delivery of drugs into the alveoli may befacilitated. Alveoli have a large surface area for drug absorption andare surrounded by an extensive capillary network which facilitates rapidpassage of drugs into the pulmonary circulation. Furthermore, becauseblood returning from the lungs is pumped directly to the systemicarterial circulation, drugs inhaled into the alveoli have the potentialto reach target organs very rapidly. Of particular importance is thatdrugs delivered in this manner reach their target site without beingexposed to potentially degrading conditions in the gastrointestinaltract and without undergoing modification by first pass metabolism inthe liver. Thus, it is desirable to provide a new route ofadministration for drug amines that rapidly produces peak plasmaconcentrations of the compounds. This invention provides a route ofadministration to accomplish this goal.

[0005] One type of inhalation aerosol is a condensation aerosol formedfrom vaporization of compounds. The use of vaporized drugs, thus,provides a method of maximizing alveolar delivery and rapidly deliveringdrugs to target organs. However, the heat required to vaporize a drugoften also generates degradation products, which may decrease theefficacy of the thermal vapor and are undesirable to be delivered to thepatient. Particularly, the salt form of a drug is expected to lower acompound's vapor pressure, and consequently raise its vaporizationtemperature and potentially increase the amount of degradation productthat is likely generated. Thus, a method that enhances drugvolatilization without the formation of a substantial amount ofdegradation products with amine drug salts and a method for selectedamine drug salts suitable for use in condensation aerosol is needed.Therefore, one object of the invention is to provide a thermal vapor ofamine drug salts for inhalation therapy that does not contain asignificant amount of thermal degradation products.

[0006] Furthermore, while many drugs may be delivered in their free baseform using vaporization, such as those, for example, disclosed in U.S.application Ser. No's: 10/150,591, 10/150,267, 10/155,705 and10/152,640, some amine drugs are liquid in their free base form andthus, are not optimal in a vaporization method that uses films orcoatings to generate the aerosol. In such cases, the physical orchemical stability of the coating may be enhanced through formation ofthe drug amine salt. Thus, another object of the present invention is toprovide amine drugs with desirable properties for thermal vapordelivery.

[0007] While dry powder formulations and new liquid aerosol devices arebeing developed or are available for inhalation therapy. See forexample, U.S. Pat. No. 5,993,805 to Sutton et al.; WO 0000176 toRobinson et al.; WO 9916419 to Tarara et al.; WO 0000215 to Bot et al.;U.S. Pat. No. 5,855,913 to Hanes et al.; and U.S. Pat. Nos. 6,136,295and 5,874,064 to Edwards et al.; U.S. Pat. No. 6,131,570 to Schuster etal.; U.S. Pat. No. 5,724,957 to Rubsamen et al.; and U.S. Pat. No.6,098,620 to Lloyd et al.; U.S. Pat. Nos. 5,586,550; 5,758,637; and6,085,740 to Ivri et al.; and U.S. Pat. No. 5,938,117.

[0008] These technologies are limited, however. Dry powders requireexcipients to formulate the dry powders for appropriate delivery.Whereas with liquid aerosols, because the solubility of many drugcompounds in water or other solvents suitable for liquid aerosoldelivery is low, the total quantity of drug that can be delivered in asingle breath is quite small. Thus, there is a need for condensationaerosol of amine drug salts that overcome these limitations. Thisinvention provides such a means.

[0009] These and other features of the invention will be described indetail below. All publications, patents, and patent applicationsreferred to herein are incorporated herein by reference in theirentirety.

SUMMARY OF THE INVENTION

[0010] The present invention provides methods and reagents for selectingand generating novel amine drug condensation aerosols and vapors, aswell as methods of delivering amine drug aerosols, novel thermal vaporcompositions, and methods for generating therapeutically effectiveinhalation doses of condensation aerosols.

[0011] In one aspect, the invention provides a method for selectingamine drugs salts for use in forming a condensation aerosol comprising:

[0012] a. dissolving or suspending a salt form of an amine drug in asolvent,

[0013] b. coating the suspended or dissolved salt form of the amine drugon a substrate,

[0014] c. heating the coated substrate to form a compound vapor,

[0015] d. cooling the vapor to form aerosol particles,

[0016] e. collecting the aerosol particles,

[0017] f. analyzing the collected particles to determine the purity ofthe aerosol particles; and

[0018] g, selecting the amine drug based on a decomposition index lessthan 0.15.

[0019] Other preferred embodiments are those wherein the amine drug saltis selected from the group consisting of an antibiotic, anticonvulsant,antidepressant, antiemetic, antihistamine, antiparkinsonian drug,antipsychotic, anxiolytic, drugs for erectile dysfunction, drugs formigraine headache, drugs for the treatment of addiction, musclerelaxants, non-steroidal anti-inflammatory, opioid, or analgesics.

[0020] Amine drug salts selected by the above method can be used to formnovel amine drug condensations aerosols having preferably a mass medianaerodynamic diameter between the range of 1 and 5, and less than 10%amine drug decomposition products. More preferable embodiments have amass median aerodynamic diameter between the range of 1 and 3.

[0021] In another aspect of the invention, a method of delivering anamine drug in an aerosol form is provided, comprising:

[0022] a. heating a coating, which includes an amine drug salt on asubstrate contained in a device to a temperature sufficient tovolatilize the amine drug from the coating,

[0023] b. by said heating, forming a amine drug vapor, and

[0024] c. during said heating, drawing air through said device,condensing said vapor to form aerosol particles containing less than 10%degradation products of the compound.

[0025] In more preferred embodiments of the method, the coating of theamine drug salt used has a thickness between about 0.5 and 20 μm and theaerosol particles generated have a mass median aerodynamic diameterbetween about 1 and 5 micrometers. More preferably, the aerosolparticles generated have a mass median aerodynamic diameter of about 1to 3 micrometers with a geometric standard deviation of about 2.5 orless.

[0026] In a third aspect of the invention, novel thermal vapors areprovided. These thermal vapors comprise gas and amine drug aerosolparticles,

[0027] a. wherein said gas comprises an acid halide vapor, organic acidvapor, or organic acid decomposition product vapor, and

[0028] b. wherein said amine drug aerosol particles

[0029] i. comprise at least 10 micrograms of an amine drug and less than10% amine drug decomposition products relative to said total mass ofamine drug in the particles, and

[0030] ii. have a mass median aerodynamic diameter in the range 1 to 5micrometers.

[0031] These thermal vapors typically further contain a supersaturatedamine drug vapor. Preferably such vapor is warmer than ambienttemperature, and more preferably such vapor is warmer than 100° C., 200°C., 250° C., or 300° C.

[0032] In yet another aspect of the invention, a method is provided forforming a therapeutically effective inhalation does of drug amineaerosol particles with less than 10% degradation products, comprising:

[0033] a) providing a drug delivery article comprising a body definingan interior flow-through chamber having upstream and down stream chamberends and a drug supply unit contained within such chamber, wherein saiddrug supply unit comprises a heat-conductive substrate coated with acomposition comprising at least a therapeutic amount of amine drug salthaving a decomposition index less than 0.10;

[0034] b) heating said heat-conductive substrate to a temperature ofgreater than 200° C. over a period of less than 5 seconds, therebyproducing a vapor of a therapeutic dose of said amine drug salt; and

[0035] c) flowing a gas through said chamber thereby cooling said vaporto form drug amine aerosol particles.

[0036] In the preferred embodiments, the thickness of the coating ofamine drug salt on the substrate is between about 0.2 and 20 μm. Thetypical amine drug particle mass median aerodynamic diameter of theseembodiments is between about I and 5 micrometers. More preferably, theamine drug particle mass median aerodynamic diameter of theseembodiments is between about 1 and 3 micrometers. In a more preferredembodiment the thermal vapor consists essential of gas and amine drugaerosol particles.

BRIEF DESCRIPTION OF THE FIGURES

[0037]FIG. 1 is a side view showing internal details of a device forvaporizing a drug including an external chamber in accordance with thepresent invention for delivery of a drug to a mammal.

DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention provides methods for screening amine drugsalts for suitability in condensation aerosols; methods to deliveraerosols, novel vapor compositions, and methods to generatetherapeutically effective amounts of amine aerosols. To facilitateunderstanding and the practice of the invention in its many and diverseapplications, this description is organized as shown below.

[0039] I. DEFINITIONS

[0040] II. CHARACTERISTICS OF THE AMINE DRUG SALTS

[0041] III. CHARACTERISTICS OF THE THERMAL VAPOR, AEROSOL AND/ORPARTICLES

[0042] IV. METHODS

[0043] V. EXAMPLES

I. Definitions

[0044] “Acid halide” refers to HF, HCl, HBr, HI, HAt.

[0045] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0046] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0047] “Aerosol drug amine mass density” refers to the mass of drugamine per unit volume of aerosol.

[0048] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0049] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0050] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0051] “Decomposition index” refers to a number derived from an assayand described in Example 3 and 4. The number is determined bysubstracting the fractional purity of the generated aerosol from 1.

[0052] “Drug” refers to any chemical compound that is used in theprevention, diagnosis, treatment, or cure of disease, for the relief ofpain, or to control or improve any physiological or pathologicaldisorder in humans or animals. Such compounds are oftentimes listed inthe Physician's Desk Reference (Medical Economics Company, Inc. atMontvale, N.J., 56^(th) edition, 2002), which is herein incorporated byreference. The drugs are preferably other than recreational drugs. Morespecifically, the drugs are preferably other than recreational drugsused for non-medicinal recreational purposes, e.g., habitual use tosolely alter one's mood, affect, state of consciousness, or to affect abody function unnecessarily, for recreational purposes. Cocaine,amphetamine, methamphetamine, and their derivatives are recreationaldrugs specifically excluded from the term “drug”. The terms “drug” and“medication” are herein used interchangeably.

[0053] “Drug amine” refers to a drug containing a primary, secondary, ortertiary amine moiety and not a quaternary amine moiety.

[0054] “Drug amine” refers to a drug containing an amine moiety. Drugamine and “amine drug” are terms that mean the same and herein are usedinterchangeably.

[0055] “Drug amine salt” refers to a drug amine, where the amine groupis protonated by an acid to form an ammonium salt with a correspondingcounterion derived from the acid. The counterion is a pharmaceuticallyacceptable anion (e.g., Cl— or CH₃CO₂—). The drug amines from which thesalts are formed come from a variety of drug classes, including, withoutlimitation, antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, and otheranalgesics. Drug amine salt and “amine drug salt” are terms that meanthe same and herein are used interchangeably.

[0056] Examples of antibiotics from which drug amine salts are formedinclude cephalexin; cephaloglycin; cephalosporins, such as cephalosporinC; cephradine; amoxicillin; hetacillin; cyclacillin; and penicillins,such as penicillin N.

[0057] An example of anticonvulsants from which a drug amine salt isformed is tiagabine.

[0058] Examples of antidepressants from which drug amine salts areformed include amitriptyline, amoxapine, butriptyline, clomipramine,desipramine, dosulepin, doxepin, imipramine, lofepramine, medifoxamine,mianserin, mirtazapine, nortriptyline, protriptyline, trimipramine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, paroxetine, reboxetine, sertraline, tianeptine, iproniazid,isocarboxazid, moclobemide, phenyhydrazine, phenelzine, selegiline,sibutramine, tranylcypromine, ademetionine, amisulpride, amperozide,benactyzine, bupropion, idazoxan, metralindole, milnacipran, minaprine,nefazodone, nomifensine, ritanserin, roxindole, tofenacin, trazodone,tryptophan, and venlafaxine.

[0059] Examples of antiemetics from which drug amine salts are formedinclude alizapride, azasetron, benzquinamide, bromopride, buclizine,chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine,diphenidol, dolasetron, droperidol, granisetron, hyoscine,metoclopramide, metopimazine, ondansetron, perphenazine, promethazine,prochlorperazine, scopolamine, triethylperazine, trifluoperazine,triflupromazine, trimethobenzamide, and tropisetron.

[0060] Examples of antihistamines from which drug amine salts are formedinclude azatadine, brompheniramine, carbinoxamine, chlorpheniramine,clemastine, cyproheptadine, dexmedetomidine, diphenhydramine,doxylamine, hydroxyzine, cetrizine, fexofenadine, and promethazine.

[0061] Examples of antiparkisonian drugs from which drug amine salts areformed include amantadine, baclofen, biperiden, benztropine,orphenadrine, procyclidine, trihexyphenidyl, levodopa, carbidopa,selegiline, deprenyl, apomorphine, benserazide, bromocriptine, budipine,cabergoline, dihydroergokryptine, pramipexole, galanthamine, lazabemide,lisuride, memantine, mofegiline, pergolide, remacemide, and terguride.

[0062] Examples of antipsychotics from which drug amine salts are formedinclude acetophenazine, alizapride, amperozide, benperidol,benzquinamide, bromperidol, butaperazine, carphenazine, carpipramine,chlorpromazine, chlorprothixene, clocapramine, clomacran, clopenthixol,clospirazine, clothiapine, cyamemazine, droperidol, flupenthixol,fluphenazine, fluspirilene, haloperidol, mesoridazine, metofenazate,molindone, penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,zuclopenthixol, amisulpride, clozapine, melperone, olanzapine,quetiapine, and risperidone.

[0063] Examples of anxiolytics from which drug amine salts are formedinclude diazepam, alprazolam, triazolam, indiplon, zaleplon,mecloqualone, medetomidine, metomidate, adinazolam, chlordiazepoxide,clobenzepam, flurazepam, loprazolam, midazolam, azacyclonol, buspirone,captodiamine, enciprazine, flesinoxan, ipsapirone, lesopitron, loxapine,methaqualone, propanolol, tandospirone, trazadone, zopiclone, andzolpidem.

[0064] Examples of drugs for erectile dysfunction from which amine saltsare formed include cialis (IC351), sildenafil, vardenafil, apomorphine,apomorphine diacetate, phentolamine, and yohimbine.

[0065] Examples of drugs for migraine headache from which drug aminesalts are formed include almotriptan, eletriptan, alpiropride, codeine,dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometheptene,lidocaine, lisuride, metoclopramide, naratriptan, oxycodone,propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan,amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepin,fluoxetine, lisinopril, methysergide, metoprolol, nadolol,nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

[0066] Examples of drugs for the treatment of alcoholism from which drugamine salts are formed include naloxone and naltrexone.

[0067] An example of a drug for the treatment of addiction from whichdrug amine salts are formed is buprenorphine.

[0068] Examples of muscle relaxants from which drug amine salts areformed include baclofen, cyclobenzaprine, orphenadrine, quinine, andtizanidine.

[0069] Examples of nonsteroidal anti-inflammatories from which drugamine salts are formed include aceclofenac, alminoprofen, amfenac,bromfenac, carprofen, cinchophen, diclofenac, etodolac, mazipredone,meclofenamate, pirprofen, and tolfenamate.

[0070] Examples of opioids from which drug amine salts are formedinclude alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, cipramadol,clonitazene, codeine, dextromoramide, dextropropoxyphene, diamorphine,dihydrocodeine, diphenoxylate, dipipanone, fentanyl, hydromorphone,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

[0071] Examples of other analgesics from which drug amine salts areformed include apazone, benzpiperylon, benzydramine, caffeine, clonixin,ethoheptazine, flupirtine, nefopam, orphenadrine, propacetamol, andpropoxyphene.

[0072] Examples of acids used to form the drug amine salt include,without limitation, the following: hydrochloric acid; hydrobromic acid;formic acid; acetic acid; maleic acid; fumaric acid, benzoic acid, andtrifluoroacetic acid.

[0073] “Drug amine degradation product” refers to a compound resultingfrom a chemical modification of the amine. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis.

[0074] “Inhalable aerosol drug amine mass density” refers to the aerosoldrug amine mass density produced by an inhalation device and deliveredinto a typical patient tidal volume.

[0075] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0076] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0077] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0078] “Organic acid” refers to a compound, generally of less than 300grams/mole of molecular weight, containing one or more carboxylic acidfunctional groups.

[0079] “Organic acid decomposition product” refers to products resultingfrom a chemical modification of the organic acid. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation ordecarboxylation.

[0080] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0081] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0082] “Rate of drug amine aerosol formation” refers to the mass ofaerosolized, drug amine produced by an inhalation device per unit time.

[0083] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0084] “Suitable drug amine salt” refers to a drug amine salt that, whensubjected to the assay described in Example 2, provides a drug amineaerosol in greater than 85% purity.

[0085] “Thermal vapor” refers to a vapor phase, aerosol phase or mixtureof aerosol-vapor phases, formed preferably by heating. The thermal vapormay comprise a drug and optionally a carrier, and may be formed byheating the drug and optionally a carrier.

[0086] “Treatment” refers to an approach for obtaining beneficial ordesired clinical results. For purposes of this invention, beneficial ordesired clinical results include, but are not limited to, one or more ofthe following: alleviation of symptoms, diminishment of extent of adisease, stabilization (i.e., not worsening) of a state of disease,preventing spread (i.e., metastasis) of disease, preventing occurrenceor recurrence of disease, delay or slowing of disease progression,amelioration of the disease state, and remission (whether partial ortotal).

[0087] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0088] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.

II. Characteristics of The Amine Drug Salts

[0089] Preferably, the drug amine salt is a salt of a drug aminefreebase, wherein the salt of the freebase has a molecular weight ofgreater than 200 grams/mole. More preferably, the drug amine salt has amolecular weight greater than 250 grams/mole, 300 grams/mole, or 350grams/mole.

[0090] Preferably, the drug amine salt has a decomposition index lessthan 0.15. More preferably, the drug amine salt has a decompositionindex less than 0.10. Most preferably, the drug amine salt has adecomposition index less than 0.05. Preferably, the composition that isheated comprises at least 10 percent by weight of drug amine salt. Morepreferably, the composition comprises at least 20 percent, 30 percent,40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent,95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of drug amine salt.

[0091] Typically, the drug amine salt is a salt of a drug amine from oneof the following classes: antibiotics, anticonvulsants, antidepressants,antiemetics, antihistamines, antiparkisonian drugs, antipsychotics,anxiolytics, drugs for erectile dysfunction, drugs for migraineheadaches, drugs for the treatment of alcoholism, drugs for thetreatment of addiction, muscle relaxants, nonsteroidalanti-inflammatories, opioids, and other analgesics.

[0092] Typically, where the drug amine salt is a salt of an antibiotic,it is selected from a salt of one of the following compounds:cephalexin; cephaloglycin; cephalosporins, such as cephalosporin C;cephradine; amoxicillin; hetacillin; cyclacillin; and penicillins, suchas penicillin N.

[0093] Typically, where the drug amine salt is a salt of ananticonvulsant, it is selected from a salt of one of the followingcompounds: gabapentin, tiagabine, and vigabatrin.

[0094] Typically, where the drug amine salt is a salt of ananticonvulsant, it is selected from a salt of tiagabine.

[0095] Typically, where the drug amine salt is a salt of anantidepressant, it is selected from a salt of one of the followingcompounds: amitriptyline, amoxapine, butriptyline, clomipramine,desipramine, dosulepin, doxepin, imipramine, lofepramine, medifoxamine,mianserin, mirtazapine, nortriptyline, protriptyline, trimipramine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, paroxetine, reboxetine, sertraline, tianeptine, iproniazid,isocarboxazid, moclobemide, phenyhydrazine, phenelzine, selegiline,sibutramine, tranylcypromine, ademetionine, amisulpride, amperozide,benactyzine, bupropion, idazoxan, metralindole, milnacipran, minaprine,nefazodone, nomifensine, ritanserin, roxindole, tofenacin, trazodone,tryptophan, and venlafaxine.

[0096] Typically, where the drug amine salt is a salt of an antiemetic,it is selected from a salt of one of the following compounds:alizapride, azasetron, benzquinamide, bromopride, buclizine,chlorpromazine, cinnarizine, clebopride, cyclizine, diphenhydramine,diphenidol, dolasetron, droperidol, granisetron, hyoscine,metoclopramide, metopimazine, ondansetron, perphenazine, promethazine,prochlorperazine, scopolamine, triethylperazine, trifluoperazine,triflupromazine, trimethobenzamide, and tropisetron.

[0097] Typically, where the drug amine salt is a salt of anantihistamine, it is selected from a salt of one of the followingcompounds: azatadine, brompheniramine, chlorpheniramine, clemastine,cyproheptadine, dexmedetomidine, diphenhydramine, doxylamine,hydroxyzine, cetrizine, fexofenadine, and promethazine.

[0098] Typically, where the drug amine salt is a salt of anantiparkisonian drug, it is selected from a salt of one of the followingcompounds: amantadine, baclofen, biperiden, benztropine, orphenadrine,procyclidine, trihexyphenidyl, levodopa, carbidopa, selegiline,deprenyl, apomorphine, benserazide, bromocriptine, budipine,cabergoline, dihydroergokryptine, pramipexole, galanthamine, lazabemide,lisuride, memantine, mofegiline, pergolide, remacemide, and terguride.

[0099] Typically, where the drug amine salt is a salt of anantipsychotic, it is selected from a salt of one of the followingcompounds: acetophenazine, alizapride, amperozide, benperidol,benzquinamide, bromperidol, butaperazine, carphenazine, carpipramine,chlorpromazine, chlorprothixene, clocapramine, clomacran, clopenthixol,clospirazine, clothiapine, cyamemazine, droperidol, flupenthixol,fluphenazine, fluspirilene, haloperidol, mesoridazine, metofenazate,molindone, penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, remoxipride,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepine,zuclopenthixol, amisulpride, clozapine, melperone, olanzapine,quetiapine, and risperidone.

[0100] Typically, where the drug amine salt is a salt of an anxiolytic,it is selected from a salt of one of the following compounds: diazepam,alprazolam, triazolam, indiplon, zaleplon, mecloqualone, medetomidine,metomidate, adinazolam, chlordiazepoxide, clobenzepam, flurazepam,loprazolam, midazolam, azacyclonol, buspirone, captodiamine,enciprazine, flesinoxan, ipsapirone, lesopitron, loxapine, methaqualone,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

[0101] Typically, where the drug amine salt is a salt of a drug forerectile dysfunction, it is selected from a salt of one of the followingcompounds: cialis (IC351), sildenafil, vardenafil, apomorphine,apomorphine diacetate, phentolamine, and yohimbine.

[0102] Typically, where the drug amine salt is a salt of a drug formigraine headache, it is selected from a salt of one of the followingcompounds: almotriptan, alpiropride, eletriptan, codeine,dihydroergotamine, ergotamine, eletriptan, frovatriptan, isometheptene,lidocaine, lisuride, metoclopramide, naratriptan, oxycodone,propoxyphene, rizatriptan, sumatriptan, tolfenamic acid, zolmitriptan,amitriptyline, atenolol, clonidine, cyproheptadine, diltiazem, doxepin,fluoxetine, lisinopril, methysergide, metoprolol, nadolol,nortriptyline, paroxetine, pizotyline, propanolol, protriptyline,sertraline, timolol, and verapamil.

[0103] Typically, where the drug amine salt is a salt of a drug aminefor the treatment of alcoholism, it is selected from a salt of one ofthe following compounds: naloxone, and naltrexone.

[0104] Typically, where the drug amine salt is a salt of a drug aminefor the treatment of addiction it is buprenorphine.

[0105] Typically, where the drug amine salt is a salt of a musclerelaxant, it is selected from a salt of one of the following compounds:baclofen, cyclobenzaprine, orphenadrine, quinine, and tizanidine.

[0106] Typically, where the drug amine salt is a salt of a nonsteroidalanti-inflammatory, it is selected from a salt of one of the followingcompounds: aceclofenac, alminoprofen, amfenac, bromfenac, carprofen,cinchophen, diclofenac, etodolac, mazipredone, meclofenamate, pirprofen,and tolfenamate.

[0107] Typically, where the drug amine salt is a salt of an opioid, itis selected from a salt of one of the following compounds: alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, cipramadol, clonitazene, codeine,dextromoramide, dextropropoxyphene, diamorphine, dihydrocodeine,diphenoxylate, dipipanone, fentanyl, hydromorphone, lofentanil,levorphanol, meperidine, methadone, meptazinol, metopon, morphine,nalbuphine, nalorphine, oxycodone, papaveretum, pethidine, pentazocine,phenazocine, remifentanil, sufentanil, and tramadol.

[0108] Typically, where the drug amine salt is a salt of an otheranalgesic it is selected from a salt of one of the following compounds:apazone, benzpiperylon, benzydramine, caffeine, clonixin, ethoheptazine,flupirtine, nefopam, orphenadrine, propacetamol, and propoxyphene.

[0109] Typically, where the drug amine salt is a salt of a stimulant, itis selected from a salt of one of the following compounds: amphetamine,brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine,fenfluramine, mazindol, methyphenidate, pemoline, phentermine, andsibutramine.

[0110] Typically, the drug amine salt is a hydrochloric acid salt,hydrobromic acid salt, formic acid salt, acetic acid salt, maleic acidsalt, fumaric acid salt, benzoic acid salt or trifluoroacetic acid salt.

[0111] Typically, the drug amine salt is selected from a group of saltsconsisting of brompheniramine maleate, carbinoxamine maleate,chlorpheniramine maleate, cyproheptadine hydrochloride, pyrilaminemaleate, buproprion hydrochloride, trimipramine maleate, tranylcyprominehydrochloride, protriptyline hydrochloride, apomorphine diacetatehydrochloride, buprenorphine hydrochloride, nicotine dihydrochloride,nicotine sulfate, apomorphine hydrochloride, diphenhydraminehydrochloride, mexiletine hydrochloride, and nicotine hydrochloride..

[0112] Typically, the drug amine salt is a mono- or di-salt (e.g.,monohydrochloride or dihydrochloride).

III. Characteristics of The Thermal Vapor, Aerosol and/or Particles

[0113] Typically, the particles comprise at least 5 percent by weight ofdrug amine. Preferably, the particles comprise at least 10 percent byweight of drug amine. More preferably, the particles comprise at least20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent,80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5percent, 99.9 percent or 99.97 percent by weight of drug amine.

[0114] Typically, the condensation aerosol particles have a mass of atleast 0.01 mg. Preferably, the aerosol particles have a mass of at least0.05 mg. More preferably, the aerosol particles have a mass of at least0.10 mg, 0.15 mg, 0.2 g or 0.25 mg.

[0115] Typically, the particles comprise less than 10 percent by weightof drug amine degradation products relative to drug amine. Preferably,the particles comprise less than 5 percent by weight of drug aminedegradation products relative to drug amine. More preferably, theparticles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of drugamine degradation products relative to drug amine.

[0116] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0117] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 micrometers. More preferably, the particles have a massmedian aerodynamic diameter between the range of 1-3 micrometers.

[0118] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of greater than 0.01micrometers. Preferably, the particles have a mass median aerodynamicdiameter of greater than 1 micrometers.

[0119] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.3, 2.0, 2.0or 1.8.

[0120] Typically, the delivered aerosol has an inhalable aerosol drugmass density of between 0.1 mg/L and 100 mg/L. Preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.1 mg/L and 75mg/L. More preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.1 mg/L and 50 mg/L.

[0121] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0122] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0123] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0124] Typically, the thermal vapor comprises a gas and amine drugaerosol particles,

[0125] a. wherein said gas comprises an acid halide vapor, organic acidvapor, or organic acid decomposition product vapor, and

[0126] b. wherein said amine drug aerosol particles

[0127] i. comprise at least 10 micrograms of an amine drug and less than10% amine drug decomposition products relative to said total mass ofamine drug in the particles, and

[0128] ii. have a mass median aerodynamic diameter in the range 1 to 5micrometers.

[0129] Typically, the thermal vapor also includes supersaturated aminedrug vapor. Generally, the supersaturated amine drug vapor is at atemperature greater than 200° C. More preferably, the temperature of thesupersaturated amine drug vapor is greater than 300° C.

[0130] Preferably, the composition that is heated comprises at least 10percent by weight of drug amine salt. More preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drugamine salt.

[0131] A number of gases can be used in the invention, including but notlimited to air, nitrogen, argon, and carbon dioxide. The preferredembodiment includes air as a gas.

[0132] Typically, between 0.1 mg and 100 mg of drug amine are deliveredto the mammal in a single inspiration. Preferably, between 0.1 mg and 75mg of drug amine are delivered to the mammal in a single inspiration.More preferably, between 0.1 mg and 50 mg of drug amine are delivered ina single inspiration.

[0133] Typically, the delivered condensation aerosol results in a peakplasma concentration of drug amine in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02 or 0.01 h.

IV. Methods

[0134] Selection of Drug Amine Salts for Condensation Aerosols

[0135] In one aspect the present invention provides a method ofselecting an amine drug salt suitable for use in forming a condensationaerosol, comprising

[0136] a. dissolving or suspending an amine drug salt in a solvent,

[0137] b. coating the suspended or dissolved amine drug salt on asubstrate,

[0138] c. heating the coated substrate to form a compound vapor,

[0139] d. cooling the vapor to form aerosol particles,

[0140] e. collecting the aerosol particles,

[0141] f. analyzing the collected particles to determine the purity ofthe aerosol particles;

[0142] and

[0143] g, selecting the amine drug based on a decomposition index lessthan 0.15.

[0144] Substrates on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, substrates provide a large surface to volume ratio(e.g., greater than 100 per meter) and a large surface to mass ratio(e.g., greater than 1 cm² per gram).

[0145] A substrate of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0146] A number of different materials are used to construct thesubstrates. Classes of such materials include, without limitation,metals, inorganic materials, and polymers. The following are examples ofthe material classes: aluminum, silver, gold, stainless steel, copperand tungsten; silica, glass, silicon and alumina; graphite;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0147] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Chromatography resins such as octadecyl silanechemically bonded to porous silica are exemplary coated variants ofsilica.

[0148] In a preferred embodiment of the invention, the substrate ismetallic. In more preferred embodiments, the substrate is aluminum foilor stainless steel.

[0149] The heating of the drug amine salt compositions is performedusing any suitable method. Examples of methods by which heat can begenerated include the following: passage of current through anelectrical resistance element; absorption of electromagnetic radiation,such as microwave or laser light; and, exothermic chemical reactions,such as exothermic solvation, hydration of pyrophoric materials,oxidation of combustible materials and heating on a hot plate.

[0150] The substrate is typically heated to a temperature of at least200° C. to vaporize the amine drug salt. In more preferred embodiments,the substrate is heated to at least 300° C., 350° C., or 400° C.

[0151] The particles are collected by means known to those of skill inthe art; preferred means include collection in a vial or on a filter.

[0152] The resultant particles are analyzed by any technique known bythose of skill in the art., including those disclosed below underAnalysis of Drug Amine Aerosols. Preferred methods of analyses includereverse-phase HPLC by absorption of UV light, typically at 225 nm andLC/MS.

[0153] A drug amine salt was preferred for aerosolization where thepurity of the drug isolated by this method was greater than 85%. Such adrug amine salt has a decomposition index less than 0.15. Thedecomposition index was arrived at by substracting the fractional purity(i.e., 0.85) from 1.

[0154] Formation and Delivery of Drug Amine Containing Aerosols

[0155] Any suitable vaporization method is used to form the aerosols ofthe present invention. A preferred method, however, involves heating athin coating or film of a composition comprising a drug amine salt toform a vapor, followed by cooling of the vapor such that it condenses toprovide a drug amine comprising aerosol (condensation aerosol). Thecomposition is heated in one of two forms: as pure active compound(i.e., pure drug amine salt); or, as a mixture of active compound and apharmaceutically acceptable excipient.

[0156] Typically, upon heating of the composition, in addition tovaporizing the drug amine, the acidic component of the salt or adecomposition product thereof is also vaporized. For example, uponheating of a salt of a drug amine and an acid, wherein there is anequilibrium between the cationic drug amine plus the anionic acid andthe neutral form of the drug amine plus the neutral acid, the acid mayvaporize leaving behind the freebase (neutral form) of the drug aminewhich subsequently vaporizes. Such vaporization may occur at a greaterrate if the equilibrium results in a comparatively larger amount of theneutral form of the drug amine and acid, and if the neutral form of theacid has a high vapor pressure (e.g,, HCl). As such, in a preferredembodiment of the invention, the acid component of the drug salt isselected to favor such an equilibrium, or is selected for its high vaporpressure. In cases where the acid component of the drug amine salt is anorganic acid, an alternative series of events may occur, which involvesdecarboxylation of the organic acid to form carbon dioxide plus organicacid decomposition products. Such decarboxylation may leave behind thedrug amine in its freebase (neutral) form which may subsequentlyvaporize. In the case where the organic acid is, for example, lactic ortartaric acid or pyruvic acid, the acid may decompose to generateacetaldehyde in addition to carbon dioxide. In preferred embodiments ofthe invention the counterion degrades to form carbon dioxide. In otherpreferred embodiments, the counterion boils at less than 50° C., lessthan 100° C., or less than 200° C.

[0157] In a particularly preferred embodiment, an amine drug aerosol isformed and delivered by a method, comprising:

[0158] a. heating a coating, which includes an amine drug salt on asubstrate contained in a device to a temperature sufficient tovolatilize the amine drug from the coating,

[0159] b. by said heating, forming a amine drug vapor, and

[0160] c. during said heating, drawing air through said device,condensing said vapor to form aerosol particles containing less than 10%degradation products of the compound.

[0161] To deliver a compound through the thermal aerosol route withoutsignificant thermal decomposition prior to vaporizing, a key componentof the invention involves the use of a coating of the drug as a thinfilm prior to vaporizing it. Such thin film coatings generally result invaporization of drug salt amines without substantial decomposition, withthinner coatings generally resulting in less decomposition than thickercoatings. In general, coatings in the range of thickness from 0.05 to 50micrometers are preferred, with coatings in the range of thickness of0.1 to 30 micrometers more preferred, and 0.2 to 20 micrometers mostpreferred. Coatings at the thinner end of the ranges are preferred fordrug amines with a substantial tendency to decompose upon heating,whereas the thicker coatings can be employed for drug amines with lesstendency to decompose upon heating.

[0162] In addition, certain drug amines may undergo decompositionreactions that occur substantially more rapidly in the liquid phase thanin the solid phase. For such drug amines, it is particularly preferredto form amine drug salts that sublime upon heating. In a preferredembodiment of the invention, the drug salt amine sublimes at greaterthan 0.001 atm, 0.01 atm, 0.1 atm, or 1 atm of pressure.

[0163] Preferably, the drug amine salt used in the methods of theinvention has a decomposition index less than 0.10. More preferably, thedrug amine salt has a decomposition index less than 0.05. Preferably,the composition that is heated comprises at least 10 percent by weightof drug amine salt. More preferably, the composition comprises at least20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent,80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5percent, 99.9 percent or 99.97 percent by weight of drug amine salt.

[0164] Pharmaceutically acceptable excipients that are volatile ornonvolatile may be included in compositions of the methods. Volatileexcipients, when heated, are concurrently volatilized, aerosolized andinhaled with drug amine. Classes of such excipients are known in the artand include, without limitation, gaseous, liquid and solid solvents. Thefollowing is a list of exemplary carriers within the classes: water;terpenes, such as menthol; alcohols, such as ethanol, propylene glycol,glycerol and other similar alcohols; dimethylformamide;dimethylacetamide; wax;; and mixtures thereof.

[0165] Substrates on which the composition is heated are of a variety ofshapes. Examples of such shapes include, without limitation, cylindersof less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness andvirtually any shape permeated by small (e.g., less than 1.0 mm-sized)pores. Preferably, substrates provide a large surface to volume ratio(e.g., greater than 100 per meter) and a large surface to mass ratio(e.g., greater than 1 cm² per gram).

[0166] A substrate of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0167] A number of different materials are used to construct thesubstrates. Classes of such materials include, without limitation,metals, inorganic materials, carbonaceous materials and polymers. Thefollowing are examples of the material classes: aluminum, silver, gold,stainless steel, copper and tungsten; silica, glass, silicon andalumina; graphite; polytetrafluoroethylene and polyethylene glycol.Combinations of materials and coated variants of materials are used aswell.

[0168] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Chromatography resins such as octadecyl silanechemically bonded to porous silica are exemplary coated variants ofsilica.

[0169] The heating of the drug amine salt compositions is performedusing any suitable method. Examples of methods by which heat can begenerated include the following: passage of current through anelectrical resistance element; absorption of electromagnetic radiation,such as microwave or laser light; and, exothermic chemical reactions,such as exothermic solvation, hydration of pyrophoric materials andoxidation of combustible materials.

[0170] Drug amine containing aerosols of the present invention aredelivered using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating a drug amine salt containing composition to form a vapor; anelement allowing the vapor to cool, thereby providing a condensationaerosol; and, an element permitting inhalation of the aerosol. Varioussuitable heating methods are described above. The element that allowscooling is, in it simplest form, an inert passageway linking the heatingmeans to the inhalation means. The element permitting inhalation is anaerosol exit portal that forms a connection between the cooling elementand the mammal's respiratory system.

[0171] One device used to deliver the drug amine containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a down streamchamber end 102 and a upstream chamber end 104, a drug supply unit 106,a power source 108, and a mouthpiece 110.

[0172] A drug amine salt composition is deposited on a surface 112 ofthe drug supply unit 106. Upon activation of a user activated switch114, power source 108 initiates heating of the drug supply unit 106(e.g., through ignition of combustible fuel or passage of currentthrough a resistive heating element). The drug amine compositionvolatilizes due to the heating of the drug supply unit 106 and condensesto form a condensation aerosol prior to reaching the mouthpiece 110 atthe downstream chamber end of the device 102. Air flow traveling fromthe device upstream chamber end 104 to the mouthpiece 110 carries thecondensation aerosol to the mouthpiece 110, where it is inhaled.

[0173] Devices, if desired, contain a variety of components tofacilitate the delivery of drug amine containing aerosols. For instance,the device may include any component known in the art to control thetiming of drug aerosolization relative to inhalation (e.g.,breath-actuation), to provide feedback to patients on the rate and/orvolume of inhalation, to prevent excessive use (i.e., “lock-out”feature), to prevent use by unauthorized individuals, and/or to recorddosing histories.

[0174] Dosage of Drug Amine Containing Aerosols

[0175] A typical dosage of a drug amine aerosol is either administeredas a single inhalation or as a series of inhalations taken within anhour or less (dosage equals sum of inhaled amounts). Where the drugamine is administered as a series of inhalations, a different amount maybe delivered in each inhalation. The dosage amount of drug amine inaerosol form is generally no greater than twice the standard dose of thedrug amine given orally.

[0176] One can determine the appropriate dose of drug amine containingaerosols to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug amine in ananimal after its exposure to the aerosol. Mammals such as dogs orprimates are typically used in such studies, since their respiratorysystems are similar to that of a human. Initial dose levels for testingin humans is generally less than or equal to the dose in the mammalmodel that resulted in plasma drug levels associated with a therapeuticeffect in humans. Dose escalation in humans is then performed, untileither an optimal therapeutic response is obtained or a dose-limitingtoxicity is encountered.

[0177] In another aspect of the invention, a method is provided forforming an effective human therapeutic inhalation dose of drug amineaerosol particles having less than 10% degradation products and a drugamine particle mass median aerodynamic diameter between about 1 and 5micrometers, comprising:

[0178] a) providing a drug delivery article comprising a body definingan interior flow-through chamber having upstream and down stream chamberends and a drug supply unit contained within such chamber, wherein saiddrug supply unit comprises a heat-conductive substrate coated with acomposition comprising at least a therapeutic amount of amine drug salthaving a decomposition index less than 0.10;

[0179] b) heating said heat-conductive substrate to a temperature ofgreater than 200° C. over a period of less than 5 seconds, therebyproducing a vapor of a therapeutic dose of said amine drug salt; and

[0180] c) flowing a gas through said chamber thereby cooling said vaporto form drug amine aerosol particles

[0181] A number of drug delivery devices can be used including the onedescribe in FIG. 1 and above.

[0182] Preferably, the drug amine salt used in the method of theinvention has a decomposition index less than 0.10. More preferably, thedrug amine salt has a decomposition index less than 0.05. Preferably,the composition that is heated comprises at least 10 percent by weightof drug amine salt. More preferably, the composition comprises at least20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent,80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5percent, 99.9 percent or 99.97 percent by weight of drug amine salt.

[0183] The preferred coatings are those that result in vaporization ofdrug salt amines without substantial decomposition and are in the rangeof thickness from 0.05 to 50 micrometers. More preferred coatings are inthe range of thickness of 0.1 to 30 micrometers, and the most preferredthickness is in the range 0.2 to 20 micrometers.

[0184] Analysis of Drug Amine Containing Aerosols

[0185] Purity of a drug amine containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

[0186] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0187] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of drug aminedegradation products.

[0188] Particle size distribution of a drug amine containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

[0189] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0190] Inhalable aerosol drug amine mass density is determined, forexample, by delivering a drug amine-containing aerosol into a confinedchamber via an inhalation device and measuring the amount ofnon-degraded drug collected in the chamber. Typically, the aerosol isdrawn into the chamber by having a pressure gradient between the deviceand the chamber, wherein the chamber is at lower pressure than thedevice. The volume of the chamber should approximate the tidal volume ofan inhaling patient. The amount of non-degraded drug amine collected inthe chamber is determined by extracting the chamber, conductingchromatographic analysis of the extract and comparing the results of thechromatographic analysis to those of a standard containing known amountsof drug amine.

[0191] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug amine into a confined chamber via aninhalation device and measuring the number of particles of given sizecollected in the chamber. The number of particles of a given size may bedirectly measured based on the light-scattering properties of theparticles. Alternatively, the number of particles of a given size isdetermined by measuring the mass of particles within the given sizerange and calculating the number of particles based on the mass asfollows: Total number of particles=Sum (from size range 1 to size rangeN) of number of particles in each size range. Number of particles in agiven size range = Mass in the size range/Mass of a typical particle inthe size range. Mass of a typical particle in a given sizerange=π*D³*φ/6, where D is a typical particle diameter in the size range(generally, the mean boundary MMADs defining the size range) in microns,φ is the particle density (in g/mL) and mass is given in units ofpicograms (g⁻¹²).

[0192] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug amine into a confined chambervia an inhalation device. The delivery is for a set period of time(e.g., 3 s), and the number of particles of a given size collected inthe chamber is determined as outlined above. The rate of particleformation is equal to the number of 100 nm to 5 micron particlescollected divided by the duration of the collection time.

[0193] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug amine into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the mass of particulate matter collected is determined by weighingthe confined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0194] Rate of drug amine aerosol formation is determined, for example,by delivering a drug amine containing aerosol into a confined chambervia an inhalation device over a set period of time (e.g., 3 s). Wherethe aerosol is pure drug amine, the amount of drug collected in thechamber is measured as described above. The rate of drug amine aerosolformation is equal to the amount of drug ester aerosol collected in thechamber divided by the duration of the collection time. Where the drugamine containing aerosol comprises a pharmaceutically acceptableexcipient, multiplying the rate of aerosol formation by the percentageof drug ester in the aerosol provides the rate of drug aerosolformation.

[0195] The drug amine containing aerosols of the present invention aretypically used for the same indication for which they are given orally.For instance, baclofen would be used to treat parkinsons disease andfexofenadine would be used to treat allergy symptoms.

[0196] As will be apparent to those of skill in the art upon reading ofthis disclosure, the present invention provides valuable methodsrelating to amine drug aerosols. The above description of necessityprovides a limited and merely illustrative sampling of the specificcompounds, substrates, and devices features and should not be construedas limiting the scope of the invention. Other features and advantages ofthe invention will be apparent from the following examples and claims.

EXAMPLES

[0197] The following examples describe specific aspects of the inventionto illustrate the invention and also provide a description of themethods used to select amine base salts suitable for formingcondensation aerosols, and methods to generate amine drug aerosols andmeasure various physical properties of such aerosols to aid those ofskill in the art in understanding and practicing the invention. Theexamples should not be construed as limiting the invention, in anymanner.

[0198] Drug amine salts are typically commercially available from Sigma(www.sigma-aldrich.com), obtained in tablet form from a pharmacy andextracted, or synthesized using well known methods in the art.

Example 1 General Procedure A for Volatilizing Drug Amines from DrugAmine Salts General Procedure for the Preparation of a Coating Solution

[0199] The concentration of a solution for coating of the substrate wastypically 50-200 mg/ml. The amine drug salt was dissolved in anappropriate solvent. Common solvent choices included methanol,dichloromethane, and a 3:1 chloroform:methanol mixture, although DMF wasused for less soluble amine drug salts and deionized water was used foramine drug salts that were insoluble in organic solvents. Occasionallysonication or heat was necessary to dissolve the compound.

[0200] Volatilization

[0201] A solution of drug amine salt in a minimal amount of solvent wastypically coated on a piece of aluminum foil (precleaned with acetone).The solvent was allowed to evaporate. The coated foil was wrapped arounda 300 watt halogen tube (Feit Electric Company, Pico Rivera, Calif.),which was inserted into a glass tube sealed at one end with a rubberstopper. Running 60 V of alternating current (driven by line powercontrolled by a variac) through the bulb for 5-15 s or 90 V for 3.5-5 safforded a thermal vapor (including aerosol), which was collected on theglass tube walls. (When desired, the system was flushed through withargon prior to volatilization.) Reverse-phase HPLC analysis withdetection by absorption of UV light, generally at 225 nm, was used todetermine the purity of the aerosol.

Example 2 General Procedure B for Volatilizing Drug Amines from DrugAmine Salts Dip Coating

[0202] The substrate, consisting of a hollow stainless steel cylinderwith thin walls, typically having a wall thickness of 0.12 mm, diameter13 mm, and length 36 mm and conducive to resistance heating, wasdip-coated with an amine drug salt coating solution (prepared asdisclosed in Example 1) typically using a computerized dip-coatingmachine to produce a thin layer of drug on the outside of the substratesurface. Prior to using, the substrates were cleaned in dichloromethane,methanol, and acetone, then dried, and fired at least once to remove anyresidual volatile material. The substrate was lowered into the drugsolution and then removed from the solvent at a rate of typically5-25cm/sec. The substrate was then allowed to dry for 30 minutes insidea fume hood. If either DMF or a water mixture was used as a dip coatingsolvent, the substrate was vacuum dried inside a desiccator for aminimum of one hour. Once the substrate was solvent free and only thedrug remained, it was ready for volatilization. The drug-coated portionof the cylinder generally has a surface area of 8.5 cm². By assuming aunit density for the drug, the initial drug coating thickness werecalculated.

[0203] Volatilization

[0204] A dip coated substrate was placed in a surrounding glass tubeconnected at the exit end via Tygon tubing to a filter holder fittedwith a Savillex Teflon filter and the junction is sealed with paraffinfilm. The substrate was placed in a fitting which connects it to two Ifarad capacitors wired in series and controlled by a 12-volt relay. Thecapacitors were charged by a separate power source to about 16-21 voltsand all the power was channeled to the substrate by closing a switch andallowing the capacitors to discharge into the substrate. The substratewas heated to a temperature of ˜400° C. in ˜50 milliseconds. Thisheating process was done under an airflow of 15 L/min, which swept thevaporized drug aerosol into a 2 micron Teflon filter. Aftervolatilization, the aerosol captured on the filter was recovered foranalysis. Any material deposited on the glass sleeve or remaining on thesubstrate was also recovered. The recovered materials were analyzed byHPLC UV absorbance, generally at 225 nm, or alternatively at 250, 275,or 280 nm, using a gradient method aimed at detection of impurities. Thesamples were further analyzed by LC/MS to confirm the molecular weightof the drug and any degradants.

[0205] Table 1, which follows, provides data from drug aminesvolatilized using the above-recited general procedures A and B. TABLE 1Generic Dose Surface Thickness Mass coated % Name MW (mg) Method Area(μm) (mg) Yield Purity Apomor- 304 2 B 6 1.1 0.68 0.60 98.1 phine HClApomor- 388 2 A 20 1.0 1.9 1.65 94 phine HCl Diacetate Bromphenir- 435 2A 20 2.8 5.60 3.4 99.6 amine Maleate Bromphenir- 435 2 A under 20 3.26.40 3.2 100 amine argon Maleate Buprenor- 504 0.3 A 20 1.1 2.10 1.3791.4 phine HCl Buprenor- 504 0.3 A 20 0.05 0.1 0.08 98.0 phine HClBupropion 276 100 A 20 1.1 2.30 2.1 98.5 HCl Bupropion 276 100 A under20 1.1 2.30 1.8 99.1 HCl argon Buspirone 422 15 A 20 4.2 8.30 2.42 97.8HCl Carbinox- 407 4 A 20 3.9 7.70 4.8 99 amine Maleate Carbinox- 407 4 Aunder 20 3.4 6.8 3.0 100 amine argon Maleate Chlorphenir- 391 8 A 20 1.63.20 2.1 99.6 amine Maleate Chlorphenir- 391 8 A under 20 2.1 4.2 2.1100 amine argon Maleate Clemastine 460 1.34 A 20 2.9 5.70 1.8 76.6Fumarate Cyprohepta- 324 4 A 20 2.2 4.30 2.6 99.6 dine HCl Cyprohepta-324 4 A under 20 1.8 3.5 2.1 99.6 dine HCl argon Diphenhydr- 292 25 A 202.5 4.9 3.7 90.3 amine HCl Diphenhydr- 292 25 A under 20 2.6 5.2 3.993.3 amine HCl argon Enalapril 493 5 B 8 1.1 0.85 0.29 61.0 maleateFluphenazine 510 1 B 8 1.0 0.78 0.33 80.7 2HCl Hydroxyzine 448 50 A 2013.7 27.30 0.25 41.2 2HCl Hydroxyzine 448 50 A under 20 12.8 25.60 1.470.8 2HCl argon Meclizine 464 25 A 20 9.7 19.40 0.5 75.3 2HCl Meclizine464 25 A under 20 11.7 23.40 0.4 70.9 2HCl argon Mexiletine 216 200 B 80.9 0.75 0.44 99.4 HCl Nicotine HCl 198 1 A 32 3.2 10.3 5.4 99.9Nicotine 235 1 A 32 4.6 14.8 12.9 99.5 2HCl Nicotine 260 1 A 32 2.5 8.01.8 97.0 Sulfate Prochlor- 446 5 B 8 0.8 0.65 0.24 72.4 perazine 2HClProtriptyline 299 15 A 20 1.1 2.20 0.99 99.7 HCl Protriptyline 299 15 Aunder 20 1.1 2.1 1.1 99.8 HCl argon Pyrilamine 401 25 A 20 10.8 21.5010.5 93.7 Maleate Pyrilamine 401 25 A under 20 10.2 20.4 9.6 90.7Maleate argon Tranylcypro- 169 30 A 20 1.2 2.30 1.3 97.5 mine HClTranylcypro- 169 30 A under 20 1.0 2.0 1.2 97.2 mine HCl argonTrifluopera- 480 7.5 B 8 1.2 0.97 0.52 87.5 zine 2HCl Trimipra- 411 50 A20 1.2 2.40 1.6 95.9 mine Maleate Trimipra- 411 50 A under 20 1.1 2.202.1 97.4 mine argon Maleate

Example 3 General Procedure A for Screening Drug Amine Salts forAerosolization Preferability

[0206] Drug amine salt (1 mg) was dissolved or suspended in a minimalamount of solvent, such as for example, methanol. The solution orsuspension was pipeted onto the middle portion of a 3 cm by 3 cm pieceof aluminum foil. The coated foil was wrapped around the end of a 1½ cmdiameter vial and secured with parafilm. A hot plate was preheated toapproximately 300° C., and the vial was placed on it foil side down. Thevial was left on the hotplate for 10 s after volatilization ordecomposition had begun. After removal from the hotplate, the vial wasallowed to cool to room temperature. The foil was removed, and the vialwas extracted with dichloromethane followed by saturated aqueous NaHCO₃.The organic and aqueous extracts were shaken together, separated, andthe organic extract is dried over Na₂SO₄. An aliquot of the organicsolution was removed and injected into a reverse-phase HPLC withdetection by absorption of UV light, generally at 225 nm. A drug aminesalt was preferred for aerosolization where the purity of the drugisolated by this method was greater than 85%. Such a drug amine salt hasa decomposition index less than 0.15. The decomposition index wasarrived at by substracting the fractional purity (i.e., 0.85) from 1.

Example 4 General Procedure B for Screening Drug Amine Salts forAerosolization Preferability

[0207] Volatilizations were done using a setup which consists of two 1farad capacitors wired in series and controlled by a 12-volt relay. Adip coated substrate (prepared as described in Example 2) was placed ina surrounding tube connected at the exit end via Tygon tubing to afilter holder fitted with a Savillex Teflon filter and the junction issealed with paraffin film. The substrate was placed in a fitting whichconnects it to the capacitors. The capacitors were charged by a separatepower source to about 16-21 volts and all the power was channeled to thesubstrate by closing a switch and allowing the capacitors to dischargeinto the substrate. The substrate was heated to a temperature of ˜400°C. in ˜50 milliseconds. This heating process was done under an airflowof 15 L/min, which swept the vaporized drug aerosol into a 2 micronTeflon filter. After volatilization, the aerosol captured on the filterwas recovered for analysis. Any material deposited on the glass sleeveor remaining on the substrate was also recovered. The recoveredmaterials were analyzed by HPLC UV absorbance, generally at 225 nm, oralternatively at 250, 275, or 280 nm, using a gradient method aimed atdetection of impurities. The samples were further analyzed by LC/MS toconfirm the molecular weight of the drug and any degradants. A drugamine salt was preferred for aerosolization where the purity of the drugisolated by this method was greater than 85%. Such a drug amine salt hasa decomposition index less than 0.15. The decomposition index wasarrived at by substracting the fractional purity (i.e., 0.85) from 1.

Example 5 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Amine Drug Aerosol

[0208] A solution of 50-200 mg of amine drug salt per mL of solvent wasspread out in a thin layer on the central portion of a 3.5 cm×7 cm sheetof aluminum foil. The solvent was allowed to evaporate. The aluminumfoil was wrapped around a 300 watt halogen tube, which was inserted intoa T-shaped glass tube. Both of the openings of the tube were sealed withparafilm, which was punctured with fifteen needles for air flow. Thethird opening was connected to a 1 liter, 3-neck glass flask. The glassflask was further connected to a large piston capable of drawing 1.1liters of air through the flask. Alternating current was run through thehalogen bulb by application of 90 V using a variac connected to 110 Vline power. Within 1 s, an aerosol appeared and was drawn into the 1 Lflask by use of the piston, with collection of the aerosol terminatedafter 3.5-6 s. The aerosol was analyzed by connecting the 1 L flask toan eight-stage Andersen non-viable cascade impactor. MMAD of thecollected aerosol ranged between 1 and 3 microns with a geometricstandard deviation of less than 3. The number of particles collected onthe various stages of the cascade impactor was given by the masscollected on the stage divided by the mass of a typical particle trappedon that stage. The mass of a single particle of diameter D is given bythe volume of the particle, πD³/6, multiplied by the density of the drug(taken to be 1 g/cm³). The inhalable aerosol particle density is the sumof the numbers of particles collected on impactor stages 3 to 8 dividedby the collection volume of 1 L. The rate of inhalable aerosol particleformation is the sum of the numbers of particles collected on impactorstages 3 through 8 divided by the formation time.

Example 6 Drug Mass Density of Amine Drug Aerosol From Amine Drug Salts

[0209] A solution of 50-200 mg of amine drug salt per mL of solvent wasspread out in a thin layer on the central portion of a 3.5 cm×7 cm sheetof aluminum foil. The solvent was allowed to evaporate. The aluminumfoil was wrapped around a 300 watt halogen tube, which was inserted intoa T-shaped glass tube. Both of the openings of the tube were sealed withparafilm, which was punctured with fifteen needles for air flow. Thethird opening was connected to a 1 liter, 3-neck glass flask. The glassflask was further connected to a large piston capable of drawing 1.1liters of air through the flask. Alternating current was run through thehalogen bulb by application of 90 V using a variac connected to 110 Vline power. Within seconds, an aerosol appeared and was drawn into the 1L flask by use of the piston, with formation of the aerosol terminatedafter about 3.5-5 s. The aerosol was allowed to sediment onto the wallsof the 1 L flask for approximately 30 minutes. The flask was thenextracted with acetonitrile and the extract analyzed by HPLC withdetection by light absorption at 225 nm. Comparison with standardscontaining known amounts of the amine drug revealed the purity of theamine drug that had been collected in the flask, resulting in acalculatable aerosol drug mass density.

[0210] Although certain embodiments and examples have been used todescribe the present invention, it will be apparent to those of skill inthe art that changes may be made to those described embodiments andexamples without departing from the scope or spirit of the invention ofthe following claims.

What is claimed:
 1. A method of selecting an amine drug salt suitablefor use in forming a condensation aerosol, comprising a. dissolving orsuspending an amine drug salt in a solvent, b. coating the suspended ordissolved amine drug salt on a substrate, c. heating the coatedsubstrate to form a compound vapor, d. cooling the vapor to form aerosolparticles, e. collecting the aerosol particles, f. analyzing thecollected particles to determine the purity of the aerosol particles;and g. selecting the amine drug based on a decomposition index less than0.
 15. 2. The method of claim 1, wherein said substrate is metallic. 3.The method of claim 2, wherein said metallic substrate is aluminum foilor stainless steel.
 4. The method of claim 2, wherein said heating is ona hot plate.
 5. The method of claim 4, wherein said heating is to atemperature approximately about 300° C.
 6. The method of Claim 1,wherein said heating is resistance heating.
 7. The method of claim 6,wherein said heating is to a temperature of approximately about 400° C.8. The method of claim 1, wherein the amine drug salt is selected fromthe group consisting of an antibiotic, anticonvulsant, antidepressant,antiemetic, antihistamine, antiparkinsonian drug, antipsychotic,anxiolytic, a drug for erectile dysfunction, a drug for migraineheadache, a drug for the treatment of addiction, a muscle relaxant, anon-steroidal anti-inflammatory, an opioid, or other analgesic.
 9. Anaerosol comprising an amine drug from an amine drug salt selected by themethod of claim 2, wherein said amine drug salt is vaporized andcondensed to form amine drug aerosol particles having a mass medianaerodynamic diameter between the range of 1 and 3, and has less than 10%amine drug decomposition products.
 10. The aerosol of claim 9, whereinsaid amine drug salt has a molecular weight between 200 to
 600. 11. Theaerosol of claim 9, wherein said amine drug salt is selected from thegroup consisting of an antibiotic, anticonvulsant, antidepressant,antiemetic, antihistamine, antiparkinsonian drug, antipsychotic,anxiolytic, a drug for erectile dysfunction, a drug for migraineheadache, a drug for the treatment of addiction, a muscle relaxant, anon-steroidal anti-inflammatory, an opioid, or other analgesic.
 12. Amethod of delivering an amine drug in an aerosol form, comprising a.heating a coating, which includes an amine drug salt on a substratecontained in a device to a temperature sufficient to volatilize theamine drug from the coating, b. by said heating, forming a amine drugvapor, and c. during said heating, drawing air through said device,condensing said vapor to form aerosol particles containing less than 10%degradation products of the compound.
 13. The method according to claim12, wherein said coating of amine drug salt has a thickness betweenabout 0.2 and 20 μm.
 14. The method according to claim 13, wherein saidaerosol particles have a mass median aerodynamic diameter between about1 and 3 microns.
 15. The method of claim 14, wherein the amine drug saltis selected from the group consisting of an antibiotic, anticonvulsant,antidepressant, antiemetic, antihistamine, antiparkinsonian drug,antipsychotic, anxiolytic, a drug for erectile dysfunction, a drug formigraine headache, a drug for the treatment of addiction, a musclerelaxant, a non-steroidal anti-inflammatory, an opioid, or otheranalgesic.
 16. The method according to claim 15, wherein said amine drugsalt has a molecular weight between 200 to
 600. 17. A thermal vaporcomprising gas and amine drug aerosol particles, a. wherein said gascomprises an acid halide vapor, organic acid vapor, or organic aciddecomposition product vapor, and b. wherein said amine drug aerosolparticles i. comprise at least 10 micrograms of an amine drug and lessthan 10% amine drug decomposition products relative to said total massof amine drug in the particles, and ii. have a mass median aerodynamicdiameter in the range 1 to 5 micrometers.
 18. The thermal vapor of claim17, wherein said gas further comprises supersaturated drug amine vapor.19. The thermal vapor of claim 18, wherein said supersaturated drugamine vapor has a temperature of greater than 200° C.
 20. The thermalvapor of claim 17, wherein said drug amine aerosol particles have a massmedian aerodynamic diameter in the range 1 to 3 micrometers.
 21. Thethermal vapor of claim 17, wherein the amine drug is selected from thegroup consisting of an antibiotic, anticonvulsant, antidepressant,antiemetic, antihistamine, antiparkinsonian drug, antipsychotic,anxiolytic, a drug for erectile dysfunction, a drug for migraineheadache, a drug for the treatment of addiction, a muscle relaxant, anon-steroidal anti-inflammatory, an opioid, or other analgesic.
 22. Amethod of forming an effective human therapeutic inhalation dose of drugamine aerosol particles having less than 10% degradation products and adrug amine particle mass median aerodynamic diameter between about 1 and5 micrometers, comprising a) providing a drug delivery articlecomprising a body defining an interior flow-through chamber havingupstream and down stream chamber ends and a drug supply unit containedwithin such chamber, wherein said drug supply unit comprises aheat-conductive substrate coated with a composition comprising at leasta therapeutic amount of amine drug salt having a decomposition indexless than 0.10; b) heating said heat-conductive substrate to atemperature of greater than 200° C. over a period of less than 5seconds, thereby producing a vapor of a therapeutic dose of said aminedrug salt; and c) flowing a gas through said chamber thereby coolingsaid vapor to form drug amine aerosol particles.
 23. The methodaccording to claim 22, wherein the drug amine salt is a salt selectedfrom the group consisting of an antibiotic, anticonvulsant,antidepressant, antiemetic, antihistamine, antiparkinsonian drug,antipsychotic, anxiolytic, a drug for erectile dysfunction, a drug formigraine headache, a drug for the treatment of addiction, a musclerelaxant, a non-steroidal anti-inflammatory, an opioid, or otheranalgesic.